Hyperinsulinemia-induced microglial mitochondrial dynamic and metabolic alterations lead to neuroinflammation in vivo and in vitro
Numerous studies have demonstrated that type 2 diabetes (T2D) is closely linked to the occurrence of Alzheimer’s disease (AD). Nevertheless, the underlying mechanisms for this association are still unknown. Insulin resistance (IR) hallmarked by hyperinsulinemia, as the earliest and longest-lasting p...
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| Format: | Article |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2022.1036872/full |
| _version_ | 1798017966965522432 |
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| author | Xiaohan Yang Xiaohan Yang Yuan Xu Wenting Gao Li Wang Li Wang Li Wang Xinnan Zhao Gang Liu Gang Liu Kai Fan Shuang Liu Huimin Hao Siyan Qu Siyan Qu Renhou Dong Xiaokai Ma Jianmei Ma Jianmei Ma |
| author_facet | Xiaohan Yang Xiaohan Yang Yuan Xu Wenting Gao Li Wang Li Wang Li Wang Xinnan Zhao Gang Liu Gang Liu Kai Fan Shuang Liu Huimin Hao Siyan Qu Siyan Qu Renhou Dong Xiaokai Ma Jianmei Ma Jianmei Ma |
| author_sort | Xiaohan Yang |
| collection | DOAJ |
| description | Numerous studies have demonstrated that type 2 diabetes (T2D) is closely linked to the occurrence of Alzheimer’s disease (AD). Nevertheless, the underlying mechanisms for this association are still unknown. Insulin resistance (IR) hallmarked by hyperinsulinemia, as the earliest and longest-lasting pathological change in T2D, might play an important role in AD. Since hyperinsulinemia has an independent contribution to related disease progressions by promoting inflammation in the peripheral system, we hypothesized that hyperinsulinemia might have an effect on microglia which plays a crucial role in neuroinflammation of AD. In the present study, we fed 4-week-old male C57BL/6 mice with a high-fat diet (HFD) for 12 weeks to establish IR model, and the mice treated with standard diet (SD) were used as control. HFD led to obesity in mice with obvious glucose and lipid metabolism disorder, the higher insulin levels in both plasma and cerebrospinal fluid, and aberrant insulin signaling pathway in the whole brain. Meanwhile, IR mice appeared impairments of spatial learning and memory accompanied by neuroinflammation which was characterized by activated microglia and upregulated expression of pro-inflammatory factors in different brain regions. To clarify whether insulin contributes to microglial activation, we treated primary cultured microglia and BV2 cell lines with insulin in vitro to mimic hyperinsulinemia. We found that hyperinsulinemia not only increased microglial proliferation and promoted M1 polarization by enhancing the production of pro-inflammatory factors, but also impaired membrane translocation of glucose transporter 4 (GLUT4) serving as the insulin-responding glucose transporter in the processes of glucose up-taking, reduced ATP production and increased mitochondrial fission. Our study provides new perspectives and evidence for the mechanism underlying the association between T2D and AD. |
| first_indexed | 2024-04-11T16:16:14Z |
| format | Article |
| id | doaj.art-1e9f17d4957e468c92256f4b19f161c1 |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-04-11T16:16:14Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-1e9f17d4957e468c92256f4b19f161c12022-12-22T04:14:32ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2022-11-011610.3389/fnins.2022.10368721036872Hyperinsulinemia-induced microglial mitochondrial dynamic and metabolic alterations lead to neuroinflammation in vivo and in vitroXiaohan Yang0Xiaohan Yang1Yuan Xu2Wenting Gao3Li Wang4Li Wang5Li Wang6Xinnan Zhao7Gang Liu8Gang Liu9Kai Fan10Shuang Liu11Huimin Hao12Siyan Qu13Siyan Qu14Renhou Dong15Xiaokai Ma16Jianmei Ma17Jianmei Ma18Department of Anatomy, College of Basic Medical Sciences, Dalian Medical University, Dalian, ChinaDepartment of Morphology, College of Basic Medical Sciences, Dalian Medical University, Dalian, ChinaDepartment of Anatomy, College of Basic Medical Sciences, Dalian Medical University, Dalian, ChinaInstitute of Genome Engineered Animal Models for Human Disease, National Center of Genetically Engineered Animal Models, College of Integrative Medicine, Dalian Medical University, Dalian, ChinaDepartment of Anatomy, College of Basic Medical Sciences, Dalian Medical University, Dalian, ChinaCollege of Medical Imaging Laboratory and Rehabilitation, Xiangnan University, Chenzhou, ChinaKey Laboratory of Medical Imaging and Artificial Intelligence of Hunan Province, Xiangnan University, Chenzhou, ChinaDepartment of Anatomy, College of Basic Medical Sciences, Dalian Medical University, Dalian, ChinaDepartment of Anatomy, College of Basic Medical Sciences, Dalian Medical University, Dalian, ChinaNational-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, ChinaDepartment of Anatomy, College of Basic Medical Sciences, Dalian Medical University, Dalian, ChinaDepartment of Anatomy, College of Basic Medical Sciences, Dalian Medical University, Dalian, ChinaDepartment of Anatomy, College of Basic Medical Sciences, Dalian Medical University, Dalian, ChinaDepartment of Anatomy, College of Basic Medical Sciences, Dalian Medical University, Dalian, ChinaThe Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaDepartment of Anatomy, College of Basic Medical Sciences, Dalian Medical University, Dalian, ChinaDepartment of Morphology, College of Basic Medical Sciences, Dalian Medical University, Dalian, ChinaDepartment of Anatomy, College of Basic Medical Sciences, Dalian Medical University, Dalian, ChinaNational-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, ChinaNumerous studies have demonstrated that type 2 diabetes (T2D) is closely linked to the occurrence of Alzheimer’s disease (AD). Nevertheless, the underlying mechanisms for this association are still unknown. Insulin resistance (IR) hallmarked by hyperinsulinemia, as the earliest and longest-lasting pathological change in T2D, might play an important role in AD. Since hyperinsulinemia has an independent contribution to related disease progressions by promoting inflammation in the peripheral system, we hypothesized that hyperinsulinemia might have an effect on microglia which plays a crucial role in neuroinflammation of AD. In the present study, we fed 4-week-old male C57BL/6 mice with a high-fat diet (HFD) for 12 weeks to establish IR model, and the mice treated with standard diet (SD) were used as control. HFD led to obesity in mice with obvious glucose and lipid metabolism disorder, the higher insulin levels in both plasma and cerebrospinal fluid, and aberrant insulin signaling pathway in the whole brain. Meanwhile, IR mice appeared impairments of spatial learning and memory accompanied by neuroinflammation which was characterized by activated microglia and upregulated expression of pro-inflammatory factors in different brain regions. To clarify whether insulin contributes to microglial activation, we treated primary cultured microglia and BV2 cell lines with insulin in vitro to mimic hyperinsulinemia. We found that hyperinsulinemia not only increased microglial proliferation and promoted M1 polarization by enhancing the production of pro-inflammatory factors, but also impaired membrane translocation of glucose transporter 4 (GLUT4) serving as the insulin-responding glucose transporter in the processes of glucose up-taking, reduced ATP production and increased mitochondrial fission. Our study provides new perspectives and evidence for the mechanism underlying the association between T2D and AD.https://www.frontiersin.org/articles/10.3389/fnins.2022.1036872/fullhyperinsulinemiainsulin resistanceneuroinflammationAlzheimer’s diseasemicroglia |
| spellingShingle | Xiaohan Yang Xiaohan Yang Yuan Xu Wenting Gao Li Wang Li Wang Li Wang Xinnan Zhao Gang Liu Gang Liu Kai Fan Shuang Liu Huimin Hao Siyan Qu Siyan Qu Renhou Dong Xiaokai Ma Jianmei Ma Jianmei Ma Hyperinsulinemia-induced microglial mitochondrial dynamic and metabolic alterations lead to neuroinflammation in vivo and in vitro Frontiers in Neuroscience hyperinsulinemia insulin resistance neuroinflammation Alzheimer’s disease microglia |
| title | Hyperinsulinemia-induced microglial mitochondrial dynamic and metabolic alterations lead to neuroinflammation in vivo and in vitro |
| title_full | Hyperinsulinemia-induced microglial mitochondrial dynamic and metabolic alterations lead to neuroinflammation in vivo and in vitro |
| title_fullStr | Hyperinsulinemia-induced microglial mitochondrial dynamic and metabolic alterations lead to neuroinflammation in vivo and in vitro |
| title_full_unstemmed | Hyperinsulinemia-induced microglial mitochondrial dynamic and metabolic alterations lead to neuroinflammation in vivo and in vitro |
| title_short | Hyperinsulinemia-induced microglial mitochondrial dynamic and metabolic alterations lead to neuroinflammation in vivo and in vitro |
| title_sort | hyperinsulinemia induced microglial mitochondrial dynamic and metabolic alterations lead to neuroinflammation in vivo and in vitro |
| topic | hyperinsulinemia insulin resistance neuroinflammation Alzheimer’s disease microglia |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2022.1036872/full |
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